Tumour cell-derived Wnt7a recruits and activates fibroblasts to promote tumour aggressiveness

• Published in: Nature communications Vol. 7; no. 1; pp. 10305 - 14
• Main Authors: Avgustinova, Alexandra, Iravani, Marjan, Robertson, David, Fearns, Antony, Gao, Qiong, Klingbeil, Pamela, Hanby, Andrew M., Speirs, Valerie, Sahai, Erik, Calvo, Fernando, Isacke, Clare M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 18.01.2016; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 14; 14/19; 38; 38/39; 631/67/1347; 631/80/86; 64; 64/110; 64/60; 96/95; Animals; Breast Neoplasms - metabolism; Female; Fibroblasts - cytology; Fibroblasts - metabolism; Gene Expression Regulation, Neoplastic; Heterogeneity; Humanities and Social Sciences; Humans; Mice; Mice, Inbred BALB C; multidisciplinary; NIH 3T3 Cells; Science; Science (multidisciplinary); Tumors; Wnt Proteins - genetics; Wnt Proteins - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms10305

Stromal fibroblast recruitment to tumours and activation to a cancer-associated fibroblast (CAF) phenotype has been implicated in promoting primary tumour growth and progression to metastatic disease. However, the mechanisms underlying the tumour:fibroblast crosstalk that drive the intertumoural stromal heterogeneity remain poorly understood. Using in vivo models we identify Wnt7a as a key factor secreted exclusively by aggressive breast tumour cells, which induces CAF conversion. Functionally, this results in extracellular matrix remodelling to create a permissive environment for tumour cell invasion and promotion of distant metastasis. Mechanistically, Wnt7a-mediated fibroblast activation is not dependent on classical Wnt signalling. Instead, we demonstrate that Wnt7a potentiates TGFβ receptor signalling both in 3D in vitro and in vivo models, thus highlighting the interaction between two of the key signalling pathways in development and disease. Importantly, in clinical breast cancer cohorts, tumour cell Wnt7a expression correlates with a desmoplastic, poor-prognosis stroma and poor patient outcome. How cancer-associated fibroblasts become activated to support metastasis is not well understood. Here, Avgustinova et al . show that tumour cell-derived Wnt7a activates TGFβ signaling in fibroblasts, inducing them to remodel the microenvironment to the state, which promotes tumour invasiveness and metastasis.